Intravenous infusion is carried out for the purpose of supplying nutrients to maintain a patient's life when oral or nasal feeding is impossible or insufficient, when the digestion and absorption functions of the patient are in a poor state, even if such a feeding means can be carried out, or when the passage of food through the digestive tract makes the patient's condition or disease more serious. Examples of commercially available infusion preparations include a sugar intravenous infusion which contains reducing sugars and the like, amino acids and the like, an electrolyte infusion liquid which contains electrolytes and the like, a fat emulsion which contains a plant oil and the like, and a vitamin mixture. These infusion preparations are appropriately selected depending on the condition of the patient and are mixed upon use. However, mixing these preparations at the time of their use requires complex handling and, above all things, raises the problem of microbial contamination. With the aim of overcoming such problems, various infusion preparations, in which some of the aforementioned infusion liquids are mixed in advance, have been proposed. Infusion preparations which contain sugars, amino acids, electrolytes and a fat emulsion, all being essential nutrients to be supplied, are especially useful from a clinical point of view.
However, since these sugar infusion liquids, amino acid infusion liquids, electrolyte infusion liquids and fat emulsion are different from one another in terms of the conditions for their stable existence, various problems arise when they are mixed, and the mixture becomes useless in many cases.
For example, because of its unstable nature, a fat emulsion is apt to form bulky fat particles and to cause phase separation (creaming) when mixed with other infusion liquids. In particular, divalent cations contained in an electrolyte infusion liquid cause aggregation and disintegration of fat emulsion particles.
In the case of an electrolyte infusion liquid, since it contains calcium and phosphoric acid as essential components to maintain the balance of electrolytes, it is apt to form calcium phosphate by the reaction of calcium with phosphoric acid and therefore to generate turbidity and precipitation. In order to prevent the formation of turbidity and precipitation, such an electrolyte infusion liquid is usually adjusted to a low pH value (less than pH 5). When such a electrolyte infusion liquid is mixed with an amino acid infusion liquid, the pH of the mixture increases to the amino acid pH value because of the strong buffer action of amino acids, thus requiring a large quantity of acidic materials (for example, hydrochloric acid, acetic acid and the like) to keep the pH value at a low level. However, acidic materials can be used only in a limited amount because a large quantity of acid spoils the balance of the infusion components. As a consequence, the pH value of the mixture of electrolyte and amino acid infusion liquids cannot be lowered to a satisfactory level, thus resulting in the generation of turbidity and precipitation at the time of heat sterilization of the mixture.
In addition, when a mixture of an amino acid infusion liquid with a sugar infusion liquid is sterilized by heating, considerable coloring occurs due to the Maillard's reaction.
As described above, it is difficult to prepare a storable infusion preparation which contains a sugar, amino acids, electrolytes and a fat emulsion, in advance, because mixing these different types of infusion liquids or emulsions causes various problems such as precipitation, denaturation, coloring and the like. Because of these problems, a fat emulsion, a sugar infusion liquid, an amino acid infusion liquid and an electrolyte infusion liquid are ordinarily mixed upon use. As a consequence, an infusion preparation has been desired which contains sugars, amino acids, electrolytes and a fat emulsion and can be stably stored.
Under these circumstances, the present inventors have conducted intensive studies on the development of a preparation method of a stable infusion preparation which contains sugars, amino acids, electrolytes and a fat emulsion. They have found that preparations containing the above components in a certain combination can be stably stored and an infusion preparation containing sugars, amino acids, electrolytes and a fat emulsion can be easily obtained, upon use, without suffering from precipitation, denaturation, coloring and other problems. More specifically, it has been found that the above problems can be solved by putting an infusion liquid containing a fat emulsion and sugars into the first compartment of a container having two compartments which are separated by a separation means, putting an infusion liquid containing amino acids and electrolytes into its second compartment, sterilizing said container, preserving it in this state, and mixing the infusion liquids contained in the first compartment and the second compartment by removing the separation means upon use (cf. JP-A-5-31151).
It has become common to give various vitamins during treatment with total parenteral nutrition (TPN). In this instance, vitamins are added to TPN admixture upon clinical use. In order to further improve the above-described newly developed infusion preparation containing sugars, amino acids, electrolytes and a fat emulsion, it is desirable to develop TPN admixture in a more perfect form containing vitamins, in advance, thereby saving the step of adding vitamins upon clinical use.
However, vitamins are usually unstable and a certain combination of vitamins can cause decomposition of one of the vitamins or can make the liquid turbid. For example, the present inventors have found that the solution becomes turbid when folic acid is mixed with vitamin C, and that vitamin C promotes decomposition of vitamin B.sub.12. Therefore, it is necessary to pay attention to the combination use of vitamins. Vitamins are roughly divided into two groups: a water-soluble group and a fat-soluble group. These two groups are different from each other in physicochemical properties. In particular, many water-soluble vitamins are unstable.
An investigation has been made regarding the composition of vitamins to be added into the above-described first compartment (fat+sugars) and the composition of vitamins to be added into the second compartment (amino acids+electrolytes). Further, by modifying the manner of addition, an infusion preparation containing stable vitamins can be obtained without affecting stability of sugars, amino acids, electrolytes and a fat emulsion. Thus, the present invention has been completed.